Pulmonary hypertension (PH), or pulmonary arterial hypertension (PAH), is a disease characterized by increased pulmonary artery pressure and pulmonary vascular resistance. Harrison's Principles of Internal Medicine, 15th ed., pp. 1506-1507 (McGraw-Hill, 2001). Left untreated, PH “usually has a dismal prognosis culminating in right ventricular failure and death.” Ulrich, S., et al., Swiss Med. Wkly 137:73-82, 73 (2007).
In 2003, the World Health Organization (WHO) sponsored the development of guidelines, called the “Venice classification,” which are now used to classify types of PH. http://www.tracleer.com/default.asp?page=CouldHave_WHO (accessed Jun. 29, 2007). The first type, WHO Group 1.1, is idiopathic pulmonary arterial hypertension (IPAH). This refers to PAH that occurs at random, without an apparent cause. IPAH used to be called “primary pulmonary hypertension” or PPH. Id.
The second type, WHO Group 1.2, is familial pulmonary arterial hypertension (FPAH). With this type of PAH, a faulty gene is passed on through the family, which causes the PAH to develop over time. It is estimated that at least 6 to 10 percent of PAH cases occur in families where at least one other person has had the disease. Id.
The third type, WHO Group 1.3, is pulmonary arterial hypertension associated with other diseases or conditions (APAH). This used to be called “PAH secondary to other conditions” or Secondary PAH. This category includes PAH associated with collagen vascular disease or “connective tissue disease” (e.g., scleroderma (SSc)-including CREST syndrome-lupus (SLE)), congenital systemic-to-pulmonary shunts (congenital heart disease), portal hypertension, HIV infection, drugs and toxins, and other diseases and disorders (e.g., thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy). Id.
The fourth type, WHO Group 1.4, is pulmonary arterial hypertension associated with significant venous or capillary involvement, and includes pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH).
The fifth and final type, WHO Group 1.5, is persistent pulmonary hypertension of the newborn. Id.
Drugs currently used to treat PH include pulmonary vasodilators, calcium channel blockers, and inhibitors of platelet aggregation. The Merck Manual, 17th ed., pp. 1703-4 (Merck Research Laboratories, 1999). Diuretics, nitric oxide, phosphodiesterase 5 inhibitors (e.g., sildenafil) and endothelin receptor antagonists (ERAs) are also used for its treatment. Ulrich, S., et al., Swiss Med. Wkly 137:73-82, 76-77 (2007). Endothelin receptor antagonists work by binding to the ETA and/or ETB receptor sites in the endothelium and vasculature smooth muscle, thereby preventing the neurohormone endothelin-1 (ET-1) from binding to these same receptor sites and triggering vasoconstriction. Id. at 76-77. An example of an ERA is bosentan (TRACLEER®).
Other methods of treating PH have been investigated. For example, selective serotonin reuptake inhibitors (SSRIs) reportedly reverse PH in rats. Id. at 79. These compounds, which are widely used to treat depression, affect the reuptake of the neurotransmitter serotonin (5-HT).
Serotonin is synthesized in two steps from the amino acid tryptophan. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed., p. 270 (McGraw-Hill, 2001). The first step is rate-limiting, and is catalyzed by the enzyme tryptophan hydroxylase (TPH), which has two known isoforms: TPH1, which is expressed in the periphery, and TPH2, which is expressed primarily in the brain. Walther, D. J., et al., Science 299:76 (2003). Mice genetically deficient for the tph1 gene (“knockout mice”) have been reported. In one case, the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. Id. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. Côté, F., et al., PNAS 100(23):13525-13530 (2003). Recently, TPH knockout mice were studied in a hypoxia-induced pulmonary arterial hypertension model. Morecroft, I., et al., Hypertension 49:232-236 (2007). The results of those studies suggest that TPH1 and peripheral serotonin “play an essential role in the development of hypoxia-induced elevations in pulmonary pressures and hypoxia-induced pulmonary vascular remodeling.” Id. at 232.